This application is a 371 of PCT/EP00/00834 filed Feb. 2, 2000.
The present invention relates to a method for producing [1,1xe2x80x2:4xe2x80x2,1xe2x80x3]-terphenyl compounds substituted in the 4xe2x80x3 position.
4xe2x80x3-Alkoxyterphenyl-4-carboxylic acids whose alkoxy group contains an alkyl radical of medium chain length are used in conjunction with the echinocandin B macrocycle as building blocks for producing active ingredients with antibiotic, in particular antifungal, properties.
These active ingredients display a novel principle of action and are therefore of particular interest (WO 94/25050 and EP 0 561 639).
The 4xe2x80x3-substituted p-terphenyl to be emphasized from the group thereof is 4xe2x80x3-n-pentoxy-[1,1xe2x80x2:4xe2x80x2,1xe2x80x3]-terphenyl-4-carboxylic acid, which leads, after coupling with the echinocandin B macrocycle, to a product with excellent properties.
WO 94/25050 describes a multistage method for producing 4xe2x80x3-n-pentoxy-[1,1xe2x80x2:4xe2x80x2,1xe2x80x3]-terphenyl-4-carboxylic acid (cf. pages 28 and 29 part A, part B and part C).
In a first step, 4xe2x80x2-bromo-4-hydroxybiphenyl is reacted with an n-pentyl halide to give the corresponding 4xe2x80x2-bromo-4-n-pentoxybiphenyl. The 4xe2x80x2-bromo-4-n-pentoxybiphenyl is reacted in a second step with n-butyllithium at xe2x88x9278xc2x0 C. to form, by transmetallation, 4xe2x80x2-lithium-4-n-pentoxybiphenyl which, in another step likewise at xe2x88x9278xc2x0 C., is reacted with triisopropyl borate. Hydrolysis and work-up result in 4xe2x80x2-n-pentoxybiphenyl-4-boronic acid which is reacted in further steps with 4-iodobenzoic acid in a standard Suzuki coupling. The 4xe2x80x3-n-pentoxy[1,1xe2x80x2:4xe2x80x2,1xe2x80x3]-terphenyl-4-carboxylic acid is obtained as crude product which is purified by chromatography on silica gel.
The mode of synthesis is depicted diagrammatically in simplified form below 
WO 94/25050 states yields only for the stages (part A and part B) up to formation of 4-(4-n-pentyloxyphenyl)phenylboronic acid. There is no statement of yield in part C, which relates to the production of 4xe2x80x3-n-pentoxy-[1,1xe2x80x2:4xe2x80x2,1xe2x80x3]-terphenyl-4-carboxylic acid.
EP 0 561 639 discloses the production of methyl 4xe2x80x3-n-pentoxy-[1,1xe2x80x2:4xe2x80x2,1xe2x80x3]-terphenyl-4 carboxylate using the aforementioned reaction steps 2, 3 and 4, employing methyl 4-iodobenzoate in place of 4-iodobenzoic acid in step 4. The yield of 4xe2x80x2-n-pentoxybiphenyl-4-boronic acid is 44% and in the reaction thereof with methyl 4-iodobenzoate is 64% (cf. statements on page 26, table 15 and 16, in each case second line across), which means that the overall yield is only 28.2% based on 4xe2x80x2-bromo-4-n-pentoxybiphenyl.
The method described above has several disadvantages. On the one hand, it is necessary to start from a very pure 4xe2x80x2-bromo-4-hydroxybiphenyl, which ought to contain the minimum amount of Br positional isomers in order to comply with the required isomer quality in the final product. On the other hand, the transmetallation in step 2 is rather complicated because it must be carried out at very low temperatures. If this reaction is not maintained in a particular temperature range and/or if the reaction times are too long, the corresponding 4,4xe2x80x3-di-n-pentoxy-[1,1xe2x80x2:1xe2x80x3,4xe2x80x3,1xe2x80x3xe2x80x2]-quaterphenyl is produced as a result of dimerization. This compound can, however, be removed from the desired final product only in a very complicated way. The reaction in step 3 is also carried out at very low temperature. A further disadvantage is that 4xe2x80x3-pentoxy-[1,1xe2x80x2:4xe2x80x2,1xe2x80x3]-terphenyl-4-carboxylic acid is evidently obtained as very impure crude product which must be purified by chromatography on silica gel.
In view of this, the object is to provide a method which avoids the disadvantages described above and can be carried out with acceptable effort.
This object is achieved by a method for producing [1,1xe2x80x2:4xe2x80x2,1xe2x80x3]-terphenyl compounds with the formula 
in which R is hydrogen or a straight-chain or branched C1-C4-alkyl radical, in particular hydrogen, a C1-C2-alkyl radical or C(CH3)3, R1 is hydrogen, a straight-chain or branched C1-C4-alkyl radical or a straight-chain or branched C1-C4-alkoxy radical, in particular hydrogen, a C1-C2-alkyl radical or C1-C2-alkoxy radical, preferably hydrogen, and R2 is hydrogen, a straight-chain C1-C12-alkyl radical, an unsubstituted phenyl radical, a phenyl radical which is substituted by one or two C1-C4-alkyl groups or C1-C4-alkoxy groups, or a radical xe2x80x94(CH2)xOR3 in which x is an integer from 1 to 4 and R3 is a straight-chain or branched C1-C4-alkyl radical, in particular a straight-chain C1-C8-alkyl radical, an unsubstituted phenyl radical or a radical xe2x80x94(CH2)xOR3, in which x is an integer from 1 to 4 and R3 is a straight-chain or branched C1-C4-alkyl radical, preferably a straight-chain C1-C6-alkyl radical or a radical xe2x80x94(CH2)xOR3 in which x is an integer from 1 to 2 and R3 is a straight-chain or branched C1-C4-alkyl radical.
It comprises reacting a metal aryl of the formula 
in which A is a monovalent metal or MeX, where Me is a divalent metal and X is Cl, Br or I, and R2 is A or a trisubstituted silyl radical, or has the meaning indicated in formula (1), excepting hydrogen, with a boric ester at xe2x88x9280 to 40xc2x0 C. in the presence of an inert solvent, converting the reaction product by hydrolysis into a boronic acid of the formula 
reacting the boronic acid, a boronic anhydride obtainable from boronic acid by elimination of water, or a mixture of boronic acid and boronic anhydride, with an alcohol, and reacting the boronic ester formed thereby with a biphenyl compound of the formula 
in which R and R1 have the meaning indicated in formula (1), and D is Cl, Br, I, O3Sxe2x80x94CnF2n+1, where n is an integer from 1 to 4, or N2+Yxe2x88x92 where Yxe2x88x92 is ClO4xe2x88x92, BR4xe2x88x92 or HSO4xe2x88x92, at 40 to 180xc2x0 C. in the presence of a catalyst and of a polar solvent.
The method of the invention is depicted diagrammatically below in simplified form 
The metal aryl of the formula (2) can be prepared be reacting a benzene derivative appropriately halogenated in the p position for example with Mg or an Li alkyl. There is no formation of a quaterphenyl compound which can be separated from the desired final product only with difficulty. The reaction of the metal aryl with boric ester does not in any case require the low temperatures indicated in WO 94/25050. Grignard compounds allow a reaction at distinctly higher temperatures than indicated in WO 94/25050.
A metal aryl of the formula (2) in which A is Li, Na, K, MgX or ZnX, in particular Li, MgX or ZnX and X is Cl, Br or I, in particular Cl or Br, is normally employed.
The method is particularly simple when a metal aryl of the formula (2) in which A is MgCl, MgBr or MgI, in particular MgCl or MgBr, preferably MgCl, is employed.
As already mentioned above, a metal aryl of the formula (2) in which R2 is A or a trisubstituted silyl radical, or has the meaning indicated in the compound of the formula (1), but in this case cannot be hydrogen, is employed.
If it is intended to produce a terphenyl compound of the formula (1) in which R2 is hydrogen, it is possible to start from a metal aryl (2) in which R2 is A or the trisubstituted silyl radical, and to obtain the appropriate phenolic terphenyl compound by the subsequent work-up of the reaction product.
The trisubstituted silyl radical in the metal aryl is a radical SiR4R5R6 in which the radicals R4, R5 and R6 are identical or different and are a phenyl radical or a C1-C4-alkyl radical, in particular are the same and are a C1-C4-alkyl radical. The silyl radical acts as protective group which can easily be eliminated after the reaction to form the appropriate phenolic group. A particularly suitable trisubstituted silyl radical is the Si(CH3)3 radical.
A boric ester B(ORxe2x80x2)3 in which Rxe2x80x2 is identical to or different from one another and is a straight-chain or branched C1-C8-alkyl radical, a phenyl radical which is unsubstituted or substituted by one or two C1-C4-alkyl groups or C1-C4-alkoxy groups, in particular a straight-chain or a branched C1-C4-alkyl radical, a phenyl radical which is unsubstituted or substituted by one or two C1-C4-alkyl groups, preferably a straight-chain or branched C1-C4-alkyl radical or an unsubstituted phenyl radical, particularly preferably a straight-chain or branched C1-C4-alkyl radical, is employed.
Since the boric esters whose Rxe2x80x2 radicals are identical can be obtained particularly readily, the boric esters of the aforementioned type employed in a large number of cases will have identical Rxe2x80x2 radicals. Examples of such boric esters are trimethyl borate, triethyl borate, tri-n-propyl borate, triisopropyl borate, tri-n-butyl borate and triisobutyl borate.
The reaction of the metal aryl with the boric ester is, as already mentioned at the outset, carried out at xe2x88x9280 to +40xc2x0 C., in particular xe2x88x9270 to 10xc2x0 C., preferably xe2x88x9240 to 0xc2x0 C. The inert solvent used is, for example, a dialkyl ether having 1 to 4 carbon atoms in each alkyl radical, a cycloaliphatic ether having 4 to 5 carbon atoms in the ring, for example tetrahydrofuran or 1,4-dioxane, a formaldehyde dialkyl acetal, a 1,2-dialkyl glycol ether having 1 to 4 carbon atoms in each alkyl radical, a mixture thereof or a mixture thereof with toluene, in particular a dialkyl ether having 1 to 4 carbon atoms in each alkyl radical, tetrahydrofuran, a 1,2-dialkyl glycol ether having 1 to 4 carbon atoms in each alkyl radical, a mixture thereof or a mixture thereof with toluene, preferably tetrahydrofuran, dibutyl glycol ether, methyl tert-butyl ether, diethyl ether, diisopropyl ether, di-n-butyl ether a mixture thereof or a mixture thereof with toluene.
The reaction of the boric ester with the metal aryl leads to a salt-like adduct (borate salt). After the reaction is complete, the reaction product which contains, were appropriate, the radical A or the trisubstituted silyl radical as radical R2, and any unreacted metal aryl which is still present, are decomposed by bringing the reaction mixture into contact with water or a water/ice mixture. The hydrolysis of the reaction product takes place very quickly, as does that of the metal aryl, because both the salt-like adduct and the metal aryl react very rapidly with water even at low temperatures. This leads to formation of the boronic acid (3), and salts derived from the reaction product and, where appropriate, from hydrolyzed metal aryl which is likewise still present are produced.
In order to dissolve salts, in particular basic salts, the resulting aqueous mixture is acidified, for example by adding a mineral acid, in particular hydrochloric acid or sulfuric acid. It is advisable to adjust a pH of from 0 to 4, in particular 0.5 to 3, preferably 1 to 2, to ensure complete dissolution of the salts.
A phase separation is then carried out, and the organic phase containing the inert solvent and the boronic acid is separated off. If required, the phase separation can be assisted by adding a suitable inert solvent, for example ether, methylene chloride, chloroform, toluene, chlorobenzene.
The organic phase which has been separated off is mixed with water in order to dissolve any salts still present, and the inert solvent and the solvent employed where appropriate to assist the phase separation are distilled off.
This results in the boronic acid as a solid. It is filtered off and dried. If the drying is carried out at temperature xc2x130, in particular xc2x150xc2x0 C., the boronic acid starts to eliminate water to form the corresponding anhydride. Formation of the boronic anhydrides depends on the one hand on the temperature level, and on the other hand on the time during which the boronic acid is exposed to the temperature. High temperatures and long exposure times favor formation of boronic anhydrides.
If it is desired to obtain the boronic acid, it is advisable to carry out the drying at low temperatures and under vacuum.
It is also possible to hydrolyze the boronic anhydride for example with an aqueous alkali and to liberate the boronic acid by subsequent acidification of the aqueous solution containing salt of boronic acid.
In a large number of cases there is formation of a mixture of boronic acid and boronic anhydride. The boronic anhydride comprises cyclic anhydrides, in particular trimeric boronic anhydride. It is also possible in some circumstances for mixtures of anhydrides possibly to form. The boronic acid, the boronic anhydride and the mixture of boronic acid and boronic anhydride can be, if required, purified by recrystallization in a suitable solvent for example aliphatic, cycloaliphatic and/or aromatic hydrocarbons.
In the following step, the boronic acid, the boronic anhydride or the mixture containing boronic acid and boronic anhydride is reacted with an alcohol. This esterification takes place by conventional methods. It is unnecessary to add a catalyst, for example an acid. It is possible that the boronic acid, the boronic anhydride or the mixture of boronic acid and boronic anhydride acts as catalyst. The esterification is normally allowed to proceed at 50 to 150xc2x0 C., in particular 60 to 140xc2x0 C.
In order to favor the reaction, it is advisable to remove the water formed as a result of the esterification. This can take place, for example, by azeotropic distillation to remove water or by addition of dehydrating agents, for example orthoformic esters. Suitable entrainers for azeotropic removal of water are, for example, aliphatic or aromatic hydrocarbons, chlorinated aliphatic or aromatic hydrocarbons, ethers or ketones. Without making any claim to completeness, mention may be made of pentane, hexane, heptane, cyclopentane, cyclohexane, toluene, xylene, ethylbenzene, mesitylene, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, chlorobenzene, dichlorobenzene, chlorotoluene or dichlorotoluene as entrainers.
The alcohol employed is a C1-C8 alkyl alcohol, a C2-C6-alkane-1,2-diol, a C3-C6-alkane-1,3-diol, a C4-C6-alkane-1,4-diol or 1,2-dihydroxybenzene, in particular a C1-C8-alkyl alcohol, a C2-C6-alkane-1,2-diol or a C3-C6-alkane-1,3-diol, preferably a C1-C4-alkyl alcohol, a C2-C4-alkanediol or a C3-C5-alkane-1,3-diol.
Examples of alkyl alcohols are methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, n-pentanol, 2-methylpentanol, n-hexanol, 2-ethylhexanol, in particular methanol, ethanol, n-propanol, i-propanol, n-butanol and i-butanol.
Examples of suitable alkanediols are ethylene glycol, propane-1,3-diol and 2,2-dimethylpropane-1,3-diol (neopentyl glycol).
The reaction with the alcohol results in formation of the corresponding boronic ester, which is then reacted with the biphenyl compound of the formula (4) in the presence of a catalyst, of an acid-biding agent and of a polar solvent.
However, in place of the boronic ester, it is also possible to employ the boronic acid of the formula (3), the boronic anhydride obtainable from the boronic acid by elimination of water, or the mixture of boronic acid and boronic anhydride, in this reaction and thus dispense with the preparation of the boronic ester by reaction of the boronic acid, of the boronic anhydride or of the mixture of boronic acid and boronic anhydride with the alcohol.
The reaction of the boronic ester or of the boronic acid, the boronic anhydride or the mixture of boronic acid and boronic anhydride takes place xe2x80x94as already mentionedxe2x80x94at 40 to 180xc2x0 C., in particular 50 to 130xc2x0 C., preferably 60 to 120xc2x0 C. Acid-binding agents which can be used are amines, for example, aliphatic amines, in particular trialkylamines, basic salts of organic and inorganic acids, in particular alkali metal salts and alkaline earth metal salts of organic and inorganic acids, for example Na acetate, K acetate, Na3PO4, K3PO4, NaHCO3, KHCO3, Na2CO3, K2CO3, MgCO3, CaCO3, or alkali metal oxides, alkali metal hydroxides, alkaline earth metal oxides, alkaline earth metal hydroxides, for example NaOH, KOH, Mg(OH)2 or Ca(OH)2.
Very suitable acid-binding agents have proved to be alkali metal bicarbonates, alkali metal carbonates, alkaline earth metal bicarbonates and alkaline earth metal carbonates, in particular Na2CO3 and K2CO3, preferably Na2CO3. The biphenyl compound of the formula 4 which is particularly employed is that in which R is hydrogen or a straight-chain or branched C1-C4-alkyl radical, in particular hydrogen, a C1-C2-alkyl radical or C(CH3)3, preferably CH3 or C(CH3)3, R1 is hydrogen or a straight-chain or branched C1-C4-alkyl radical or C1-C4-alkoxy radical, in particular hydrogen, a C1-C2-alkyl radical or C1-C2-alkoxy radical, and D is Cl, Br, I or N2+Yxe2x88x92, in particular Cl, Br or I, preferably Br or I.
If is possible to use as polar solvent a protic and aprotic dipolar solvent, in particular an alcohol, a sulfoxide, a sulfone, an amide and, where appropriate, water or a mixture thereof. Examples of alcohols are straight-chain or branched C1-C4-alkyl alcohols, ethylene glycol, polyetheylene glycols of the formula HOxe2x80x94(CH2xe2x80x94CH2xe2x80x94O)nH with n=2 to 1,000 or mixtures of these alcohols with one another or with water, in particular ethylene glycol, mixtures of C1-C4-alkyl alcohols with ethylene glycol or with polyethylene glycols or with water, preferably mixtures of methanol and polyethylene glycols, methanol and ethylene glycol or butanol and water.
Examples of sulfoxides are dimethyl sulfoxide and diethyl sulfoxide.
Mention should be made of sulfolane, (thiolane dioxide) as representative from the sulfone series, and of dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide and N-methylpyrrolidone as representatives of the amides series.
In a number of cases it is also possible to employ mixtures of alcohols, sulfoxides, sulfolane and/or amides, which may also contain water where appropriate.
Suitable catalysts are palladium or a palladium or nickel compound. It is possible to employ Pd metal, Pd(O) complex compounds, Pd(II) complex compounds, Ni(O) complex compounds and Ni(II) complex compounds, in particular complex compounds which contain phosphines, preferably trisubstituted phosphines such as tri-n-butylphosphine, tri-tert-butylphosphine, triphenylphosphine (PPh3).
Examples of Pd(O) complex compounds are Pd(PPh3)4, Pd(dba)2.
Examples of Pd(II) complex compounds are PdCl2(PPH3)2, PdBr2(PPh3)2, PdCl2(Rxe2x80x3CN)2PdBr2(Rxe2x80x3CN) with Rxe2x80x3=phenyl, methyl, PdCl2(dppf), PdBr2(dppf) with dppf=1,1xe2x80x2-bis(diphenylphosphino)ferrocene, PdCl2(COD), PDBr2(COD) with COD=cycloocta-1,5-diene.
Examples of Ni(O) complex compounds are Ni(PPh3)4 and examples of Ni(II) complex compounds are NiCl2(PPh3)2, NiBr2(PPh3)2, NiCl2dppf and NiBr2dppf.
It is also possible to employ Pd(II) compounds or Ni(II) compounds, for example corresponding salts, together with the phosphines. In this case, the corresponding complex compounds are formed in situ.
Palladium compounds are particularly suitable, for example PdCl2, Pd(acetate)2.
In the production of [1,1xe2x80x2,4xe2x80x2,1xe2x80x3]-terphenyl-4-carboxylic acids (Rxe2x95x90H in formula (1)) it is advisable for the reaction product formed in the reaction of the biphenyl compound (4) to be treated with water and an acid, in particular a mineral acid, preferably HCl or H2SO4, in order to bring about or complete hydrolysis of the salts which are formed. It has proved suitable in a number of cases to carry out the hydrolysis at elevated temperatures, for example at 30 to 100xc2x0 C., in particular at 60 to 90xc2x0 C.
The present invention also relates to the compounds 4-n-pentoxyphenylboronic acid 
trimeric 4-n-pentoxyphenylboronic anhydride 
glycol ester of 4-n-pentoxyphenylboronic acid 
and neopentyl glycolester of 4-n-pentoxyphenylboronic acid 
The following examples describe the invention in detail without restricting it.
Experimental part
Preparation of the starting material